Antimalarial agents and method of



' giving the :cornespondingia'cylnitrlle (VII) Patented Apr. 29, 1952PATENT ,OF-FICE ANTIMALARIAL AGENTS AND METHOD OF PREPARING THEM George.H.'1';Hit'chings and PeterByrom-Russell, Tuckahoe; and Elvira A:FalcoUNewRochelle,

I N. Y., assignors toBur-rolu'ghsT-Wellcome & Co.

- Application'December 30,1950,

Serial No. 203,791

This inventionalrelatess to new antimalarial v agents and to a method ofpreparing them.

This-application. is a cbntlnuation-inepart oi whichirdes'ci' ibes 'a'novelmethodformic-preparatlon of certain 4-amino-5 arylpyrimidines. It ia particular object of-*the1 present invention to describe a specificclass of, those substances which have outstandingantimalarial"properties. The compounds ofthe'present' invention may berepresented by the formula riszwhere xsis zaix-rhalogenatom, Y isselected 'fIOIIi It: thezcl-ass; :consistingv ofar hydrogem and halogenatoms, and R. is selected"fromith'e class consist ing of hydrogen andalkyl radicalscontaining 1 s. to 4% carbon atoms.

The compositions of the present invention' are prepared by thecondensation of an a-phenyl-salkyl-fi-alkoxyacrylonitrile with guanidineaccording to the formulas shown below:

III The a-phenyl -ealkoxy;ese alkylacrylomtriles may be. synthesizedinctheliollowingr way: A phenylacetonitrile (V) is 'preparedgfrom :aisea..1eoted benzyl chloride (IV).-.. $Ihisis thengaeylated by treatmentwith anl acyl ester :(VI') in-themresence-pf a'basie catalyst 'suchas analkali alkoxide,

6 Claims; (Cl. 260-256A) 1212101111 co -pending applicatidnserial:Numhei 1'68,'156

o, :The a-phenyl aracylacetonitrile (VII) may also befwritten. in-th'etautomeric form VIII, which j is perhaps best named as an a-phenylfi-hydroxyewalkylacrylonitrile. The substance represented ;,,by theformulas VII=andVIII on treatment with fanalkylating'agent, MIX),preferably a diazoalkane or-anxorthoester, gives the desired a-Ephenyl-B-alkoxy fl-alkylacrylonitrile (II).

latter. as shown above is-condensed with guani- The i ne to give thedesiredpyrimidine; "Tl1e'--alkyl 5' radicals RPan'd R1 inthe "formulasabove are rlelimirrated" in subsequent *reactions, moreover ri'ouslowerf'alkyl groups behave in the'same mannerand are-regarded asessentiallyequivalentfbjr thepurposes of the presentinvention.

j'TI'IBTOHOWiIlg examples illustrate the teachings of the presentinvention but in no way limit its :scope as defined in the claims.

EXAMPLE 1 m -Fluofophenylaeetonitrile m-Fluorotoluene gr) was refluxedwith sulfuryl chloride (67.5" g.) in the presence of benz'oyl peroxide(0.5 g.) When the evolution of hydrogen chloride was-complete the oilwas washed with water once;:-then refluxedwith potassium yanide MZg'm.)in: ethanol ml;) andwater into water, theoil extracted with ether andwashed well with water. On distillation it boiled;sateen/lammuomacetmtitrile The above nitrlle (13.5 g.) and ethylacetate(8.8 g.) were added to a solution of sodium (2.3 g.) in ethanol (30cc.). The mixture was heated for 5 hours. The whole was then poured intowater, any oily matter removed with ether and the aqueous solution madeacid with The ketonitrile separated, and was recrystallized from ether(petroleum ether) as needles M. P. 117-120".

2,4-diamino-S-m-fluorophenyl- 6-methylpyrimidine The above ketonitrile('7 g.) was treated with diazomethane (from gm. nitrosomethyl urea) inether. The ether was removed and treated with guanidine (1 mol) inalcohol. After heating on a steam bath for 3 hours the alcohol wasevaporated and strong sodium hydroxide was added. The product wasfiltered offand recrystallized from ethanol-water. M; P. 237-238",

Calcd for: C, 60.2; H, 5.2.

EXAMPLE 2 2,4-diamino-5-m-chZorophenyZ-6-methylpyrimidinea-Acetyl-m-chlorophenylacetonitrile (9.7 g.) was reacted withdiazomethane to give a-III- chlorophenyl-c-methoxy-c-methylacrylonitrile. This was then reacted with guanidine (from 4.7 gms. ofthe hydrochloride) in ethanol. The product was worked up as in theprevious examples. After recrystallization from ethanol it melted at219-220.

Calcd for: C11H11N4Cl: N, 24.1. Found: N, 23.9.

EXAMPLE 3 2,4-diamino-5-m-bromophenyl-6-methylpyrimidine Prepared froma-acetyl-m-bromophenylacetonitrile as above. On recrystallization fromethanol water it melted at 235-237.

EXAMPLE 4 2,4-diamino-5-(3'4'-dichlorophenyl) 6-methylpyrimidinea-Acetyl-3'4'-dichlorophenylacetonitrile (M. P. 161-163) (11.4 g.) washeated with methylorthoacetate ml.) The low boiling products wereremoved so long as they continued to be formed.

Then the orthoester was removed by distillation in vacuo. The productsolidified, on recrystallization from ethanol, it formed plates .M. P.

. 71-74 (CnHsONClz: Calcd N, 5.8. Found: N,

6.0). This a-3,4'-dichlorophenyl-o-methoxy-B- methylacrylonitrile wascondensed with guanidine (from 4.7 gm. of the hydrochloride) in theusual manner. The diaminopyrimidine separated after 2'hours heating.After crystallization from ethanol it melted at 274275.

Calcd for C11H1oN4C122 N, 20.9. Found: N, 21.2.

EXAMPLE 5 2 4-diamino-5- (34' dichlorophenyl) -6- ethylpyrimidine Thiscompound was prepared as in the previous example. It melted at 229-232,after recrystallization from ethanol water.

EXAMPLE 6 2:4-diamino-5-(34 dichZorophenyD-G-npropyl pyrimidine As abovefrom a-n-butyryl 3'4 dichlorophenylaceto nitrile (M. P. 101). Afterrecrystalliza- C11H11N4F. C, 60.5; H, 5.0.v Found:

tion from benzene/ligroin mixtures it melted at 174-176.

Calcd for: C13H14N4Cl2: C, 52.5; H, 4.7; N, 18.9. Found: C, 52.8; H,6.8; N, 18.11.

EXAMPLE 7 2:4-diamino-5-(34' dichZorophenyD-fi-n- 1 butylpyrimidinePrepared as above from a-n-valeryl-34'-dichlorophenyl acetonitrile. Itmelted at 193-195. Calcd for: C14H1sN4Cl2I C, 54.1; H, 5.2. Found: C,53.8; H, 5.0.

EXAMPLE 8 2:4-diamino-5-(3'4 dibromophenyl) 6 ethyl pyrimidine Wasprepared as above from a-propionyl-34' dibromophenyl acetonitrile. Afterrecrystallization from alcohol itmelted at 250252.

EXAMPLE 9 2 4-diamiizo-5- (3-bromo-4'-chlorophenyl) Y G-meihylpyrimidine wherein X is a halogen atom, Y is selected from the groupconsisting of hydrogen and halogen, and. R is selected from the classconsisting of hydrogen and alkyl radicals containing 1 to 4 carbonatoms.

2. 2,4 diamino 5 (3'4'-dichloropher1yl)- 6-methylpyrimidine.

3. 2,4 diamino 5 (34-dichlorophenyl) G-ethylpyrimidine.

4. 2,4 diamino 5 (3 4-dic hlorophenyl)- V fi-propylpyrimidine.

5. 2,4 diamino 5 methylpyrimidine. 6. 2,4 diamino 5 (3'-bromo-4'-chloromchlorophenyl 6- phenyl) -6-m'ethyl pyrimidine.

GEORGE H. HITOHI'NGS." .PETER' BYROM RUSSELL.

ELVIRA A. FALCO.

No references cited.

1. A 2,4-DIAMINO-5-PHENYL-6-ALKYLPYRIMIDINE OF THE FORMULA